Many pregnancy-associated disorders, including IUGR and pre-eclampsia, stem from abnormal placental development. Evidence in humans as well as animal models suggests that babies born from these pregnancies are at increased risk of hypertension, cardiovascular diseases, diabetes, and stroke later in life. In the US alone, it is estimated that the combined short and long-term financial costs related to these pregnancies are approximately 7 billion dollars per year. Importantly, each of these defects appears to be specific to a particular cell layer in the placenta, implying that each one relates to specific cell lineage origins. For example, early onset IUGR is associated with defects in placental nutrient-transporting cells whereas pre-eclampsia is associated with defects in invasive trophoblast cells that fail to remodel maternal arteries. Previous studies have shown that oxygen is an important mediator of trophoblast differentiation. Hypoxia inducible factor-1 alpha (HIF-1a) is a critical component of the cellular oxygen-sensing machinery and is essential for placental formation and embryonic survival. Endogenous HIF-1a is active under low oxygen (hypoxic) conditions, but becomes rapidly inactivated at arterial levels of oxygen, which allows trophoblast differentiation to occur. Prolonged HIF-1a activity inhibits trophoblast differentiation in culture and is associated with pregnancy- associated disorders. In this proposal, we utilize novel approaches to target specific placental cell lineages in order to investigate the role of placental HIF-1a in controlling trophoblast differentiation. This study will provide novel gene targeting vehicles and evaluate the importance placental HIF-1a activity in regulating the development of the individual trophoblast lineages necessary for appropriate placental development and normal embryonic growth. The long term objective of our research program is to determine the oxygen signaling mechanisms that regulate trophoblast differentiation, placental development, embryogenesis and maternal well being. PUBLIC HEALTH RELEVANCE: Normal placental development is essential for any successful pregnancy. Understanding how oxygen sensing regulators control normal placental development will help us understand how pregnancy-associated disorders arise, can be detected, and treated.